The overall goal of this project is to identify patterns of brain function that contribute to or result from dependence on drugs, and to suggest leads in the development of new treatment methods. Our research strategies involve the use of positron emission tomography (PET) to evaluate the effect of various drugs of abuse and cognitive activation on brain activity using cerebral metabolic rates for glucose using [F-18]fluorodeoxyglucose and regional cerebral blood flow using [O-15]-water and and magnetic resonance imaging (MRI) to evaluate structural sequelae of drug abuse. The prefrontal cortex and its connections to limbic structures modulate particular aspects of executive cognitive and emotional regulatory functions that may be impaired in drug abusers, e.g., impulse control, decision-making, sustained attention, risk taking, and arousability. Performance of abstinent drug abusers (N=21) and nonuser control participants (N=20) in the Emotional Stroop, an impulsivity continuous performance task (CPT) and a vigilance CPT revealed similar performance during simple tasks that measured vigilance, impulsivity and emotional interference, but drug abusers showed stronger skin conductance responses. Drug abusers performed more poorly on the Gambling and Rogers Decision Making Tasks, suggesting relative deficits in sensitivity to consequences and increased risk taking; drug abusers also showed significantly less increase in skin conductance than controls during these tasks. Drug abusers exhibited lower heart rates throughout performance on all tasks. We concluded that complex tasks involving decision-making, sensitivity to consequences and emotional regulation discriminated between drug abusers and controls. As risky decision-making is a hallmark behavioral phenotype of drug abuse, an understanding of its biological bases might inform efforts to develop therapies for addictive disorders. We therefore paired a cognitive task that measures this function (Rogers Decision-making Task) with measures of regional cerebral perfusion (PET-[O-15]-water) to identify brain structures or circuits that may underlie deficits in this type of decision-making in abstinent drug abusers (> 3 months) and healthy control subjects. The drug abusers showed greater risk-taking and heightened sensitivity to rewards than the control subjects. They also exhibited task-related deactivation of the left pregenual anterior cingulate cortex, whereas the control subjects showed activation. In the drug abuser group, performance on the task negatively correlated with activation in the right amygdala, left anterior cingulate gyrus, left lateral orbitofrontal cortex, and left parietal lobule, but positively correlated with activation in the right insula. Drug abuse severity was related positively to right medial orbitofrontal activity. No significant correlations were found between activation and task performance of control subjects. The different associations between task-related regional perfusion and risky decision-making, comparing the two groups, suggest an abnormal response in a distributed network of corticolimbic regions in drug abusers responding to this type of cognitive challenge. Methadone maintenance is the primary treatment for opiate addiction, but controversy surrounds the merits of its use in long-term treatment. Fifteen methadone-free (6-24 months) opiate abusers, twelve opiate abusers receiving methadone maintenance (stable dose over 6 months), and thirteen control subjects participated in this study. Methadone-withdrawn subjects had lower relative metabolic activity measured by [F-18]fluorodeoxyglucose and PET than control subjects in bilateral perigenual and the left middle cingulate gyrus. In contrast, methadone-maintained subjects exhibited lower relative activity (vs. control) in the left insula, the thalamus, and the left inferior parietal lobule; however, they exceeedded control aactivity in the perigenual anterior cingulate gyrus and the right inferior parrietal lobule. Measures of depression covaried positively with relative activity in the left perigenual and mid-cingulate gyrus in methadone-withdrawn subjects; analogous associations in control subjects covaried negatively. Methadone-maintained subjects exhibited negative covariance between state measures of depression and relative activity in the right inferior parietal lobule and the right perigenual anterior cingulate, and between trait measures of depression and relative activity in the left inferior parietal lobule. Methadone maintenance ameliorates functional abnormalities in the neural circuitry sub-serving negative affective states, but depresses brain function in some regions of high opiate receptor density. We demonstrated that heavy marijuana users have performance deficits on the Iowa decision-making task, but not on the Stroop conflict task when compared to non-users. A sample of heavy marijuana users was found to have altered brain tissue composition (gray matter and white matter) in the hippocampa region and precentral gyrus on structural MR images compared to non-users using voxel-based morphometry.